Post-translational modifications of the amino-terminal ‘tail’ (as well other non-tail sites) of histone H3 are critical for multiple DNA-templated processes. Notably, H3K27 is the target of methylation by Polycomb Repressive Complex 2 (PRC2) to modulate gene transcription (and in some cases, acetylation, brought about by distinct enzyme systems. The mono-, di-, and tri-methylation states of histone H3-K27 are associated with different functions in transcriptional control. Histone H3-K27 monomethylation (or acetylation) is often associated with active transcription of genes, such as differentiation genes, that are poised for transcription (Cui et al. “Chromatin Signatures in Multipotent Human Hematopoietic Stem Cells Indicate the Fate of Bivalent Genes During Differentiation, Cell Stem Cell 4:80-93 (2009) and Barski et al., “High-Resolution Profiling of Histone Methylation in the Human Genome,” Cell 129:823-37 (2007)). In contrast, trimethylation of histone H3-K27 is largely associated with either transcriptionally repressed genes or genes that are poised for transcription when histone H3-K4 trimethylation is in cis (Cui et al. “Chromatin Signatures in Multipotent Human Hematopoietic Stem Cells Indicate the Fate of Bivalent Genes During Differentiation, Cell Stem Cell 4:80-93 (2009); Kirmizis et al. “Silencing of Human Polycomb Target Genes is Associated with Methylation of Histone H3 Lys 27,” Genes Dev 18:1592-1605 (2007); Bernstein et al. “A Bivalent Chromatin Structure Marks Key Developmental Genes in Embryonic Stem Cells,” Cell 125:315-26 (2006).
The overexpression of genes in the PRC2 complex has been associated with a number of cancers, including, for example, metastatic prostate cancer (Crea et al., “Pharmacologic Disruption of Polycomb Repressive Complex 2 Inhibits Tumorigenicity and Tumor Progression in Prostate Cancer,” Mol. Cancer 10:40 (2011), breast cancer (Holm et al., “Global H3K27 Trimethylation and EZH2 Abundance in Breast Cancer Tumor Subtypes,” Mol. Oncol. [PMID:22766277 Epub] (June 2012)), bladder cancer (Raman et al., “Increased Expression of the Polycomb Group Gene, EZH2, in Transitional Cell Carcinoma of the Bladder,” Clin. Cancer Res. 11:8570-6 (2005)), gastric cancer (Matsukawa et al., “Expression of the Enhancer of Zeste Homolog 2 is Correlated with Poor Prognosis in Human Gastric Cancer,” Cancer Sci. 97:484-91 (2006)), melanoma, and lymphoma (McCabe et al., “Mutation of A677 in Histone Methyltransferase EZH2 in Human B-cell Lymphoma Promotes Hypertrimethylation of Histone H3 on Lysine 27 (H3K27),” Proc. Nat'l Acad. Sci. USA 109(8):2989-94 (2012)). The overexpression of polycomb genes and subsequent increase in PRC2 complex activity that has been reported in cancer is predicted to increase the trimethylated state of histone H3-K27 and thus result in transcriptional repression of several tumor suppressor genes (Crea et al., “EZH2 Inhibition: Targeting the Crossroad of Tumor Invasion and Angiogenesis,” Cancer Metastasis Rev. doi:10.1007/s10555-012-9387-3 (2012). Accordingly, agents capable of disrupting this cascade of events would be therapeutically useful for the treatment of cancer.